Summary CD4+ T cells represent an understudied yet important target in the design of anti-tumor therapeutic strategies aimed at re-shaping the tumor microenvironment and enhancing the function of anti-tumor CTL. Recent years have seen the implementation of immunotherapies for the treatment of melanoma and other cancers via the activation and/or rescue of tumor-specific CTLs in vivo. While these approaches are promising, response rates are low. CD4+ T cells also play a critical role in the control of tumor growth. Tumor growth is accelerated in the absence of CD4+ T cells, and the induction of anti-tumor CD4+ T cell responses can dramatically enhance the function and survival of tumor-specific CTL. Therefore, they represent an underexplored alternative therapeutic target, and little is known regarding their response to current checkpoint blockade immunotherapies. Our preliminary data indicate that in a mouse model of melanoma, tumor-specific recruitment of CD4+ T cells is acutely sensitive to the level of antigen. Low levels of tumor antigen fail to recruit even relatively high avidity CD4+ T cells into the anti-tumor response, indicating that one key factor regulating the T helper response to tumors is TCR avidity and subsequent T cell recruitment. These findings have led us to hypothesize that strategies aimed at lowering TCR activation threshold of CD4+ T cells will enhance their recruitment into the response and their anti-tumor function. We will test this hypothesis in two ways. First, we will test whether low TCR avidity T helper cells are recruited into the anti-melanoma response, as well as determine the impact of conventional checkpoint blockade (anti-PD-1 and/or anti-CTLA-4) on their recruitment and function. Second, we will determine whether targeting of Shp-1, a phosphatase that regulates the activity of a variety of TCR proximal signaling cascades, will induce lower CD4+ T cell activation thresholds in response to melanoma and improve their effector function in combination with checkpoint blockade. In our previously published studies, we have developed powerful tools that will allow us to analyze the CD4+ T cell response on a clone-by-clone basis, including a model system for analyzing CD4+ TCR repertoire development and evolution, methods for generating TCR ?retrogenic? mice using retroviral expression vectors and the two conventional TCR transgenic mice, both specific for the same antigen but with different TCR avidity. We anticipate that experiments proposed here will provide an important foundation for the design of melanoma immunotherapeutic strategies that target T helper cells.